Note on Drugs for Lung Cancer Flashcards
What type of Lung cancer are EGFR mutations typically associated with?
Adenocarcinomas
What EGFR monoclonals are used to treat lung cancer?
• what type of lung cancer are they used to treat?
• MOA?
Necitumumab Panitumumab
• Indicated in SQUAMOUS NSCLC
MOA: Competitively block binding of EFT and TGF-alpha to EGFR inhibiting receptor autophosphorylation
How is activity of Tyrosine Kinase Inhibitors, specifically EGFR, Blocked?
- Binding Site Mutation
- Increased activity of MET (phosphorylating enzyme)
- Binding of HGF to HGFR to kick of the PI3K/Akt path
When TK inhibitors loose their efficacy in a patient, what mutations (2) are likely to have occured?
• How do these mutations differ in their ability to make TKIs less effective?
Mutations that change cell sensitivity to TK singaling:
• Exon 19 (in-fram deletion)
• Point mutation in exon 21 (L858R)
Mutations (or natural varients) with Mutated ATP binding site:
• T790M
**Note: T790M may naturally occur**
What downstream mutations may be used to render anti-EGFR (mAbs or PKIs) drugs useless?
Mutatations in any downstream enzyme can render the drug ineffective
Why is it bad when genes fuse to yeild fusion proteins with ALK?
• What is the primary mutation involving the ALK gene that leads to NSCLC?
• what pathway is kicked off?
Mutations involving the formation of ALK fusion proteins leads to the formation of constitutively activated Tyrosine Kinases
• EML4-ALK is the most common (seen in non-smokers, light smoking history, and pts. with adenocarcinomas)
• MEK/ERK, PI3K, JAK-STAT path is activated
What is the relationship between VEGF, VHL, and HIF-1alpha?
VHL lets off of hypoxia inducible factor -1 (HIF-1) in hypoxic conditions typically so that HIF-1 can induce the transciption of growth factors including VEGF to reduce hypoxia
What are the down sides to using and anti-VEGF drug?
- Reduction in vasculature may reduce the distribution of concurrent chemotherapy
- Selection for the most aggressive cells may occur
What are some mutations that are seen more often in NSCLC in non-smokers than smokers?
• What is the most common in smokers?
Most common mutation in smokers:
• KRAS (30-40%)
Mutations more common among non-smokers:
• EGFR mutations
• EML4-ALK fusion
• HER2-mutations
What lung cancer patients should undergo testing for EGFR and ALK rearrangments?
ALL adenocarcinomas should undergo testing for EGFR or ALK mutations (squamous cell carcinoma testing is not currently recommended)
Why is Chemotherapy the only option in SCLC?
Metathesis occurs very early on so Chemotherapy and Radiation are the only good options
What are the conventional drugs used to treat SCLC?
Etoposide and Cisplatin or Carboplatin or…
Cisplatin + irinotecan
Cisplatin + etoposide + ifosfamide
Cyclophosphamide + doxorubicin and/or etoposide ± vincristine
What are the conventional treatment options for NSCLC?
• what is maintenance therapy for these pts?
CISPLATIN and Taxane (Paclitaxel, Docetaxel), Vinca alkaloid (vinorelbine), Gemcitabine (Ribonuc. reducase and DNA pols. inhibit), Irinotecan (topoisomerase inhibitor) or Pemtrexed (DHFR inhibitor - methotrexate analogue)
Maintainance via Pemtrexed
What lung cancer patients can you give EGFR TKIs to?
NSCLC Patients with EGFR positive genetic test
What lung cancer patients can get Bevacizumab?
Bevacizumab - NSCLC patients with non-squamous histology, no brain metastatses, or hemoptysis
T or F: Toxicities of newer targeted drugs affect nearly every organ system in the body.
True, **The majority of these drugs are administered in a continuous fashion making cumulative toxicities a COMMON event**
How do we minimize the toxicity of targeted drugs?
Surveillance and Early Management are key to minimizing treatment interruption
Afatinib
• Target
Target:
• EGFR, exon 19 del or 21 subs
Alectinib
• Target
Target
ALK
Ceritinib
• Target
• Indication?
Target:
ALK
Indication:
Patients that are intolerant to crizotinib
Crizotinib
• Target?
Target
• ALK, and HGFR
Eroltinib
• Target
Target:
EGFR, exon 19 del or 21 subs
Gefitinib
• Target
Target:
EGFR, exon 19 del or 21 sub
Osimertinib
• Target
Target:
EGFR, 790M mutation positive
What KEY toxicity is seen in patients receiving EGFR targeting drugs (mAb or TKI)?
• Who typically experiences this effect?
• Who doesn’t?
SEVERE RASH - makes sense b/c you’re inhibiting Epithelial Growth Factor
- YOUNGER MALE patients are more likely to get this rash
- Patient who smoke and have light skin pigmentation are more immune
What KEY toxicity is seen in targeted therapies towards angiogenesis?
HYPERTENSION (20%)***, Hemorrhage, Thrombosis, CARDIAC CONTRACTILE DYSFUNCTION- makes sense given that these are preventing new vessels from being formed
Damage to Matrix is not repaired as well without VEGF and we see exposure of the underlying matrix leading to Thrombosis and Hemorrhage
In patients using targeted therapies, especially TKIs, what should you advise them to do or not do?
Avoid Pregnancy - make sure they’re using contraception
Avoid Breastfeeding - concerns over neonatal drug toxicity
Tell them to report and Dematologic, Cardiac, or Pulmonary symptoms since these are common
Which tyrosine kinase inhibitors used in lung cancer target EGFR exon 19 del or 21 subs?
• 790M mutations (exon 20)?
Exon 19 del or 21 subs:
Afatinib
Eroltinib
Gefitinib
790M mutations:
Osimertinib
What Tyrosine Kinase Inhibitors used in lung cancer target ALK?
• differentiate between these on the basis of other targets.
ALK TKIs:
• Alectinib
• Ceritinib (ppl. intolerant to crizotinib)
• Crizotinib (also targets HGFR)
What are some things you should consider by the fact that TKIs are taken orally?
Some physicians use the rash induced by TKIs as an indicator that the drug is working. What should you do to ensure that the drug is staying at a constant level in their bloodstream?
To ensure consistent plasma levels advise against taking these drugs with Food or Grapefruit Juice
Bevacizumab
MOA
Adverse Effects
Contraindications
MOA
mAb that binds VEGF receptor and prevents activation
Adverse Effects
Hand-Foot syndrome, HTN, hemmorhage, cardiac dysfuncton, Thormbosis, Fistula formation
Contraindications
High Risk for Hemorrhage:
• NSCLC (especially those with squamous histology), renal cell carcinoma, colorectal cancer - causes central tumor necrosis leading to hemorrhage
Ramucirumab
MOA
Contraindications
MOA
Inhibits VEGF2 receptor
Adverse Effects
Neutropenia, HTN, Hemorrhage (monitor BP)
Contraindications
Unlike Bevicizumab, Ramucirumab is NOT contraindicated with Squamous Carcinoma NSCLC
Why do patients with functional p53 probably not respond to VEGF inhibitors as dramatically as those with a p53 mutation?
- VHL binds HIF-1alpha under normal circumstance but lets it go under hypoxic circumstances
- If hypoxia is induced then HIF-1 alpha will go ot the nucleus and transcribe VEGF HOWEVER…
- In prolonged Hypoxia p53 represses HIF-1 alpha
What is the idea behind PD-1 antibodies used in cancer treatment?
PD-1 is a receptor found on Tcells that downregulates their activity when bound to their ligand PD-1L. Many cancers upregulate PD-1L to avoid T cell recognition as foreign. Inhibiting this system is beneficial to allowing T cells “see” the cancer.
What mAb drugs work by inhibiting PD-1 receptors?
• what is the advantage to these drugs?
• what major risk is associated with taking these drugs?
Nivolumab
Pembrolizumab
*compared to TKIs, these mAbs have pretty mild effects
Major Risks:
• May induce AUTOIMMUNE disease (like pneumonitis, hypo/hyperthyroidism)
What happens when the phosphorylation step to EGFR is blocked?
Cell undergoes apoptosis
**Even with this resistance mechanisms like the binding of MET (aka HGFR) can come in a phosphorylate EGFR, or HGF can just kick off the pathway itself**
Carboplatin and Cisplatin
MOA
Toxicity
Remedy
MOA
Form DNA intrastrand crosslinks and adducts
Toxicity:
Carboplatin less toxic than cisplatin
• Nephro- and ototoxicity
• Peripheral Neuropathy
Remedy
• Amifostine is nephro-protective
• Prophylax for SEVERE N/V
**Dose Limiting Toxicity in Cisplatin = nephro and ototoxicity***
Cyclophosphamide, Ifosphamide
MOA
Toxicity
MOA:
Pro-drug of active alkylating moiety
Toxicity:
BMS, HEMORRHAGIC CYSTITIS from ACROLEIN
•Mesna = renoprotective
Docetaxel, Paclitaxel
MOA
Toxicity
MOA:
• Microtubule Stabilizer inhibiting depolymerization
Toxicity:
• Mucositis, Peripheral neuropathy, Hypersensivity
Doxorubicin
MOA
Toxicity
Protection
MOA
Intercalator, free radical generator, topo II inhibitor
Toxicity:
Red-Orange Urine, Acute cardiac arrythmia, Chronic cardiomyopathy (CHF)
Dexrazoxan = protective chelator
**Cumulative-Dose cardiotoxicity = Dose limiting**
Etoposide, VP-16
MOA
Toxicity
MOA:
• DNA-topo II complex stabilizer
Toxicity:
BMS, N/V, HYPOTENSION, hypersensitivity
Gemcitabine
MOA
Toxicity
MOA
DNA pols inhibitor via incorporation of triphosphate form during DNA systhesis
Toxicity
INTERSTITIAL PNEUMONITIS, Peripheral Neuropathy, BMS, mucositis, etc.
Irinotocan and Topotecan
MOA
Toxicity
MOA
DNA-topo I complex stabilizer
Toxicity:
ASTHENIA, BMS, N/V
Vincristine and Vinorelbine
MOA
Toxicity
MOA
Microtubule inhibitor; tubules disintegrate into spiral aggregates/protofilaments
Toxicity
VINCRISTINE - SIADH!!!
Peripheral neuropathy (less so with vinorelbine)
